Plasma kallikrein (PK), a serine protease present in plasma as the inactive zymogen precursor plasma prekallikrein (prePK), is proteolytically activated by FXIIa. In a positive feedback loop, PK proteloytically activates the zymogen FXII, leading to additional FXIIa formation, further amplifying its own activation. FXIIa also activates the zymogen FXI to active FXIa, which results in the initiation of the intrinsic (contact) pathway of blood coagulation, resulting in generation of thrombin, and cleavage of fibrinogen. Importantly, PK cleaves high molecular weight kininogen (HMWK) to generate bradykinin. Bradykinin is able to open the tight junctions between endothelial cells lining blood vessels by activating its receptors, B1 and B2, present on the endothelial cells' surface, and thus allowing fluid and plasma protein to extravasate into tissue, a condition known as increased vascular permeability. Disruption of tight junctions of the blood-brain barrier, and consequent leakage of plasma and proteins into the brain (edema) have also been associated with neurodegenerative diseases, such as Alzheimer's Disease, Parkinson's Disease, and multiple sclerosis (MS), as well as with CNS infections and brain tumors. For example, peritumoral brain edema results in poorer prognosis in patients with glioblastoma multiforme (Schoenegger K, Oberndorfer S, Eur J Neurol. 2009 July; 16(7):874-8). The increased vascular permeability caused by bradykinin formation can result in the accumulation of excess fluid (edema) in many tissues and organs in various diseases, e.g., angioedema, cystoid macular edema, diabetic macular edema, macular edema after retinal vein occlusion, cerebrovascular edema following stroke or head trauma, and capillary leak syndrome. For example, the PK inhibitor ASP-440 (known from WO 2008/016883, and U.S. Pat. No. 7,625,944) has been shown to reduce angiotensin-II-induced retinal vascular permeability, and elevated systolic blood pressure (Phipps, J. A., et al. (2009) Hypertension 53: 175-181). Elevated levels of PK in the eyes of rodents results in increased fluorescein leakage, and retinal edema, and ASP-440 inhibits plasma leakage into the retina in diabetic animals (Clermont A. C., et al. (2011) Diabetes, 60: 1590-8). Activation of prePK and the contact system has also been shown to cause anaphylaxis, e.g., in patients treated with contaminated heparin (Kishimoto, T. K., et al. (2008) N. Engl. J. Med. 358: 2457-2467).
Despite the developing body of knowledge surrounding plasma kallikrein-related diseases, there remains a need for the development of new therapeutic agents that are useful in the treatment of those diseases. Surprisingly, the present invention provides such compounds.